Skeletal muscle atrophy is a debilitating condition that commonly afflicts persons who are ill or aged. However, muscle atrophy is poorly understood and it lacks a therapy. To begin to address this problem, we will study its causes. We hypothesize that a central event in the pathogenesis of muscle atrophy is increased expression of Gadd45a (growth arrest and DNA damage inducible 45a). This hypothesis is based on several lines of evidence from our preliminary studies. First, we and others found that Gadd45a mRNA is increased by a variety of stresses that cause muscle atrophy, including immobilization, denervation, fasting and aging. Second, we found that transfection of mouse skeletal muscle with plasmid DNA encoding mouse Gadd45a was sufficient to induce myofiber atrophy. Third, we found that reducing skeletal muscle Gadd45a expression (by RNA interference targeting Gadd45a mRNA) reduced muscle atrophy in mice. These preliminary data suggest a model in which atrophy-inducing stresses increase skeletal muscle Gadd45a, which in turn promotes muscle atrophy. If this is true, then Gadd45a, its upstream regulators and its downstream mediators represent potential targets for therapies to prevent or reverse muscle atrophy in human patients. Here, we propose two aims. In Aim 1, we will investigate the upstream mechanisms that induce skeletal muscle Gadd45a expression during times of stress. In Aim 2, we will investigate the downstream mechanisms by which Gadd45a causes atrophy. Through these studies, we hope to elucidate central events in skeletal muscle atrophy, and thus identify novel therapeutic targets for a disabling condition that affects millions of patients. PUBLIC HEALTH RELEVANCE: Skeletal muscle atrophy places an enormous burden on patients, their families and society in general. The proposed research will investigate a novel and fundamental molecular pathway to muscle atrophy, expand our knowledge about skeletal muscle biology and disease, and elucidate new therapeutic targets for a debilitating and currently untreatable condition that affects millions of people.